What viral infection is most commonly associated with a cutaneous reaction when using oral Amoxicillin (amoxicillin)?

From the Guidelines

The viral infection most commonly associated with a cutaneous reaction when using oral Amoxicillin is Epstein-Barr virus (EBV). This is based on the strongest and most recent evidence from a 2022 practice parameter update published in the Journal of Allergy and Clinical Immunology 1. The study notes that treatment of patients with Epstein-Barr infection with amoxicillin or ampicillin can result in a nonpruritic morbilliform rash in 30%-100% of patients.

Key points to consider include:

• The reaction is not related to specific IgE antibodies and is postulated to require the presence of a concurrent viral infection or another underlying illness 1.
• The mechanism behind this reaction is not fully understood but appears to be related to a temporary alteration in immune function during EBV infection rather than a true allergic reaction to the antibiotic.
• Patients who develop this rash are often incorrectly labeled as having a penicillin allergy, which can unnecessarily restrict future antibiotic options.
• Healthcare providers should consider the possibility of underlying EBV infection when a patient develops a rash after starting amoxicillin, particularly if they have other symptoms consistent with infectious mononucleosis such as fever, sore throat, lymphadenopathy, and fatigue.

In terms of clinical implications, it is essential to recognize this phenomenon to avoid mislabeling patients as having a penicillin allergy and to ensure that they have access to the full range of antibiotic options in the future. Diagnostic testing for EBV can help confirm this association, and a thorough medical history and physical examination can help identify patients who may be at risk of developing this reaction.

From the FDA Drug Label

1. 5 Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash.

The viral infection most commonly associated with a cutaneous reaction when using oral Amoxicillin is mononucleosis 2.

From the Research

Viral Infection Associated with Cutaneous Reaction to Amoxicillin

• The viral infection most commonly associated with a cutaneous reaction when using oral Amoxicillin is Epstein-Barr virus (EBV) infection, particularly in patients with infectious mononucleosis 3, 4, 5, 6, 7.
• Studies have shown that the incidence of rash after amoxicillin treatment in children with infectious mononucleosis is significant, with one study reporting an incidence of 29.5% 4.
• The mechanism of this reaction is thought to be a transient virus-mediated immune alteration that sets the stage for loss of antigenic tolerance and the development of a reversible, delayed-type hypersensitivity reaction to the antibiotic 7.
• The association between EBV infection and skin manifestations, including exanthem of mononucleosis, has been well documented, and the use of amoxicillin can trigger characteristic rashes in patients with EBV infection, even when administered during the latent phase of the infection 5, 6.

Characteristics of the Cutaneous Reaction

• The cutaneous reaction to amoxicillin in patients with EBV infection can manifest as a generalized purpuric rash with target-shaped areas, erythema multiforme, or Stevens-Johnson syndrome 3, 6.
• The reaction is thought to be related to the aminobenzyl group of the side chain of amoxicillin, as patients with a positive reaction to amoxicillin often have a negative response to other beta-lactams 3.
• The incidence of rash in pediatric patients with infectious mononucleosis after treatment with amoxicillin is lower than originally reported, with one study reporting an incidence of 29.5% compared to the previously reported 90% rate for ampicillin 4.